The program's overall objectives are to conduct innovative, high impact clinical research related to understanding human stroke pathophysiology, and to evaluate novel stroke diagnostic and therapeutic strategies using MRI. Stroke is the third leading cause of death, the leading cause of long term disability in the elderly and has a monetary cost to society in excess of 40 billion dollars per year. We established a stroke research and care center at Suburban Hospital, a private community hospital in Bethesda, Maryland, consisting of an emergency response team and inpatient service staffed by neurologists, nurses, and researchers specializing in stroke and a research infrastructure centered around a state-of-the-art MRI facility. Only one therapy is approved as a treatment for stroke, the thrombolytic agent tissue plasminogen activator (tPA). Because tPA must be administered within three hours of onset it is only received by 2% of stroke patients. To increase tPA utilization the establishment of primary stroke centers has been advocated. Since establishment of our stroke center tPA therapy has increased from less than 1% to 13%, evidence that establishment of a stroke center does increase access to tPA therapy. Because MRI provides more sensitive and specific anatomical and physiological information than CT scans, we are investigating whether MRI may improve the risk to benefit ratio of tPA therapy. The first step is to demonstrate that the additional time the MRI exam takes does not lead to worse outcomes because of delayed initiation of therapy In 50 patients screened with MRI the clinical outcomes after tPA therapy were no worse and trended better than patients not screened only with CT. We completed a study comparing the sensitivity of MR to CT in the detection of hemorrhage. The purpose of this study was to determine if MR, which is superior to CT in determining the type of stroke, was at least equal to CT in determining whether the stroke was a hemorrhage. Our study confirmed that MR was at least equal to CT in sensitivity for detecting hemorrhage. Going forward this finding may eliminate the need for CT to be part of the diagnostic work-up for stroke. Our advanced imaging investigations of these patients treated with tPA have increased our understanding of the brain's response to reperfusion therapy. We are studying ways to increase and improve the utilization of more effective thrombolytic therapy in acute stroke and to break the 3-hour time barrier to thrombolytic treatment. In June 2002, we initiated a clinical trial (ROSIE - ReoPro Retavase Reperfusion of Stroke Safety study - Imaging Evaluation) that is studying the use of combination thrombolytic drugs for the treatment of ischemic stroke. In addition to looking at the use of combination drugs for the treatment of stroke, this study aims to combine MRI screening criteria with combination thrombolytic therapy to safely extend the treatment window from the current 3 hours limitation out to 24 hours. In addition, our research has revealed a potentially significant finding relative to reperfusion. Reperfusion of metabolically compromised tissue is considered the most vital therapy for acute ischemic stroke in humans. However, reperfusion may also worsen damage through the mechanisms of reperfusion injury which are partially mediated by damage to the blood-brain barrier (BBB). In the course of studying the natural progression of acute stroke in humans using MRI, we have found an imaging contrast mechanism that appears to be a result of early BBB disruption and which is associated with reperfusion, subsequent bleeding, and poor clinical outcome. We believe that this new imaging marker will lead to a better understanding of the mechanisms of reperfusion injury and provide investigators with a tool to develop therapies against for reperfusion injury.